Sulfated glycosamino glycan heparin is presently in general clinical use for postoperative subcutaneous thromboembolism prophylaxis in small doses of 3.times.5,000 IU per day. Relatively larger doses of this compound, however, are necessary in the extracorporeal circulation for the prevention of blood coagulation in treatments such as blood oxygenation, surgery using the heart-lung machine, hemodialysis, hemofiltration, hemoperfusion and plasmaphoresis. Moreover, as part of heparin therapy after a thromboembolic condition, i.e., venous thrombosis or pulmonary embolism, heparin salts are administered in daily intravenous doses of 30,000 to 40,000 IU.
After completion of the extracorporeal treatment or in the event that hemorrhagic complications develop during such a treatment, there is often a necessity to neutralize, as quickly as possible, the heparin still circulating in the cardiovascular system which may be present in relatively high concentrations. Promatine sulfate or protamine chloride has traditionally been used for heparin inactivation in such cases. A disadvantage of this treatment, however, according to D. Benayahn et al., Thrombos. Res. 32: 109, 1983, is the occurrence of a rebound phenomenon which can lead to the sudden, renewed release of heparin several hours after neutralization has occurred, particularly in the case of large heparin doses.
In German Offenlegensschrift DE-OS 31 35 814, an extracorporeal precipitation process for the specific separation of low-density lipoproteins (LDL) is described, in which heparin is added to the plasma in a very large dose at an acid pH (pH 5.05 to 5.25) to precipitate a filterable LDL-heparin complex. After the filtration of the heparinized plasma through a separation filter, the pH of the plasma from which the LDL-heparin complex has been removed is adjusted to within the physiological pH range of the patient by passing the plasma through a hemodializer, after which the plasma is administered back into the patient.
A total of approximately 100,000 heparin units/liter, however, are needed for the quantitative precipitation of the LDL-heparin complex in this extracorporeal treatment. Morover, the heparin concentration in the plasma readministered to the patient can reach levels of above 20 IU/ml, causing the patient's plasma level of heparin to reach values of about 4 to 12 IU/ml of plasma, thereby introducing an increased risk of hemorrhage.
Langer, et al. (J. Biol. Chem. 257: 7310, 1982; Sicence 217: 261, 1982) describe a process for the removal of heparin in which plasma is led through an exchanger that immobilizes heparinase from Flavobacterium heparinum at its surface. The heparin is broken down enzymatically into fragments that have, in comparison to heparin, a very minor anti-coagulative effect. For a broad application, this process requires, however, that the relatively unstable heparinase enzyme be obtained in large quantities as well as high purity and enzyme activity and that it be capable of being converted into a stable, sterile form that can be stored. Even a direct injection of the purified enzyme for the inactivation of the heparin is presently impossible for the toxicological reasons described by M. D. Klein in J. Lab. Clin. Md. 102: 838, 1983.
The binding of heparin to ion exchangers has been known for a relatively long period of time. For example, ion exchanges have been used for years in the isolation of heparin from aqueous solutions for the production of heparin from biological materials as well as for the purification of heparin fragments and heparin fractions, as described in J. P. Green, Nature 186: 472, 1960; R. H. Yue, et al., Thrombos. Haemostas, 42: 1452 ff., 1979; M. W. Piepkorn, et al., Thromb. Res. 13: 1077-1087, 1978, German Offenlegensscrift DE-OS 26 52 272; and German Ofenlegensscrift DE-OS 31 15 245.
The cited publications also contain descriptions of additional efforts to adsorb heparin from blood or blood plasma in the physiological pH range of blood or blood plasma. Due to the basic characteristics of the ion exchanger materials used, however, an undesirable, nonspecific binding of plasma proteins must always be expected in the physiological pH range. It has also been observed (E. Schmitt et al., Biomaterials 4: 309-314, 1983, and P. Ferruti et al., Biomaterials 4: 218-221, 1983) that after the binding of heparin to basic anion exchanger materials such as membranes of N,N-dimethylaminoethyl cellulose (DEAE) and poly(amidoamine) resins, a heparin desorption phenomenon can be observed in the physiological pH range.
Thus, there exists a need for a means by which heparin and its derivatives, heparin fractions, heparinoids heparin fragments, and other heparin-like substances can be quickly and substantially removed from plasma without the occurrence of more than a negligible heterogenous absorption of plasma proteins when basic anion exchanger materials of suitable composition are used for the adsorption, and without a risk of occurrence of a rebound phenomenon.